The detailed study of the chemistry and biology of complex natural products at a fundamental level provides insight that is key to understanding their mode of action and development of new therapeutics for treatment of various human ailments. This research program aims to develop efficient and concise total syntheses of structurally complex and biologically active natural products through the discovery, development, and application of new strategies and methodologies. In this program, biogenetic considerations provide inspiration for development of new generalizable strategies to rapidly build molecular complexity. A key feature of the planned syntheses is the development of new highly chemoselective and stereoselective transformations. Of particular interest is development of new methodologies allowing advanced stage functionalization using the inherent reactivity of intermediates. Targets are selected based on novelty of molecular architecture, paucity of prior synthetic studies, ample opportunities for development of new strategies and methodologies, possession of significant biological activity, and the potential for future chemical and biological mechanistic studies. This program will focus on synthetic studies of the rich family of dimeric diketopiperazine alkaloids. The core structures of these alkaloids are adjoined by either Csp3-alkyl (sp3-sp3) or Csp3-aryl (sp3-sp2) bond connectivity at quaternary stereocenters. The program will focus on potently bioactive epidithiodiketopiperazines, including the verticillin alkaloids, and will develop generalizable methodologies for rapid assembly and functionalization of dimeric diketopiperazines containing vicinal quaternary stereocenters connected via a Csp3-Csp3 bond. We will also study a late stage highly stereoselective oxidation-migration sequence using bisindole structures to access the Csp3-aryl (sp3-sp2) bond connectivity found in a variety of alkaloids. This program will result in synthetic samples of rare and precious compounds for structure validation and exploration of their chemistry and biology. Given the rich biological activity of diketopiperazines and epidithiodiketopiperazines under investigation, related intermediates and derivatives also hold great promise as mechanistic tools and new bioactive compounds, and thus will be subject to various tests through our collaborative activities.